Transformations of β-aryl-N-Cbz-α,β-didehydro-α-amino esters with hydrazine hydrate

Article abstract of DOI:10.1515/znb-2015-0221

Cyclizations of Cbz-protected α,β-didehydro-β-arylalanine esters 1 with excess hydrazine hydrate afforded mixtures of the expected 3-pyrazolidinones 2 and the unexpected 1-amino-5-benzylidenehydantoins 6 and N-Cbz-β-arylalanine hydrazides 7. Presumably, the pyrazolidinones 2 and hydantoins 6 are formed as primary products via competitive 1,2- and 1,4-addition of hydrazine hydrate followed by cyclization, whereas β-arylalanine hydrazides 7 are formed as secondary products via reductive cleavage of the C(5)-N(1) bond in pyrazolidinones 2. The overall selectivity depends on the reaction time and on the β-substituent in the starting dehydroalanine ester 1.

Full text of DOI:10.1515/znb-2015-0221

Z. Naturforsch. 2016; 71(6)b: 623–631
Miha Drev, Uroš Grošelj and Jurij Svete*
Transformations of β-aryl-N-Cbz-α,β-didehydro-
α-amino esters with hydrazine hydrate
DOI 10.1515/znb-2015-0221
applicability in industrial processes and biological activ-
ity. For example, pyrazolidinone derivatives have been
employed as dyes and photographic developers, and their
bioactivities range from antibacterial, analgesic, antipy-
retic, and anti-inflammatory to inhibition of cyclooxyge-
nase and lipoxygenase [5–8].
Received December 29, 2015; accepted January 22, 2016
Abstract: Cyclizations of Cbz-protected α,β-didehydro-
β-arylalanine esters 1 with excess hydrazine hydrate
afforded mixtures of the expected 3-pyrazolidinones 2
and the unexpected 1-amino-5-benzylidenehydantoins 6
and N-Cbz-β-arylalanine hydrazides 7. Presumably, the
pyrazolidinones 2 and hydantoins 6 are formed as primary
products via competitive 1,2- and 1,4-addition of hydrazine
hydrate followed by cyclization, whereas β-arylalanine
hydrazides 7 are formed as secondary products via reduc-
tive cleavage of the C(5)–N(1) bond in pyrazolidinones 2.
The overall selectivity depends on the reaction time and
on the β-substituent in the starting dehydroalanine ester 1.
In the last two decades, a substantial part of our
research interest has also been devoted to the chemistry of
3-pyrazolidinones [8, 9]. Within this context, we recently
*
*
reportedthepreparationof5-substituted(4R ,5R )-2-benzy-
loxycarbonylamino-3-pyrazolidinones 2 [7–11] from easily
available methyl N-Cbz-3-aryl-α,β-didehydroalaninates 1
[12, 13]. Pyrazolidinones 2 were used as key intermediates
in the synthesis of pyrazolo[1,2–a]pyrazole-based peptide
mimetics [7] and aza-deoxa analogues of d-cycloserine
Keywords: amino acids; cyclization; hydantoins; pyrazo- [11]. Aiming at the preparation of novel fused 3-pyrazoli-
lidinones; reduction.
dinones 3 via intramolecular cyclization between the aryl
group at position 5 and the amino function at position
4, we recently tried to prepare some 3-pyrazolidinones 2
with an ortho-substituted aryl group attached at position
5 (Fig. 1).
1 Introduction
We were convinced that intermediates 2 should
be easily available from the corresponding dehydroa-
laninates 1 following standard synthetic protocol [7–11].
However, the planned synthesis of target tricyclic pyrazo-
lidinones 3 (cf. Fig. 1) could not be developed, as the key
intermediates 2 could not be prepared, neither selectively
nor effectively. It turned out that reactions of N-benzylox-
ycarbonyl-3-aryl-2,3-dehydroalaninates 1 with hydrazine
hydrate did not give only the corresponding 3-pyrazoli-
dinones 2 as believed previously, but rather mixtures of
3-pyrazolidinones 2, 1-aminohydantoins 6, and 3-arylala-
nine hydrazides 7. Further experiments were performed
to obtain a closer insight into selectivity and the mecha-
nism of these ring transformations. Herein, we report the
results of this study.
α,β-Didehydro-α-amino acid derivatives are important and
useful intermediates and building blocks in organic syn-
thesis. For example, they are employed in the synthesis of
α-amino acids, peptides, and related compounds, as well
as for the preparation of various heterocyclic compounds
including natural products and their analogues [1–4].
3-Pyrazolidinones are cyclic (internal) hydrazides of
3-hydrazinopropanoic acid, which are commonly avail-
able by treatment of an α,β-unsaturated carboxylic acid
derivative with hydrazine hydrate. The importance of
3-pyrazolidinones has risen significantly, owing to their
*Corresponding author: Jurij Svete, Faculty of Chemistry and
Chemical Technology, University of Ljubljana, Večna pot 113,
SI-1000 Ljubljana, Slovenia, Fax: +386 1 2419 144,
E-mail: jurij.svete@fkkt.uni-lj.si
Miha Drev and Uroš Grošelj: Faculty of Chemistry and Chemical
Technology, University of Ljubljana, Večna pot 113, SI-1000
Ljubljana, Slovenia
Jurij Svete: Faculty of Chemistry and Chemical Technology,
University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia;
and EN-FIST, Centre of Excellence, Trg Osvobodilne fronte 13, 1000
Ljubljana, Slovenia
2 Results and discussion
Starting acrylates 1a–n were prepared from methyl
2-benzyloxycarbonylamino-2-(dimethoxyphosphoryl)
acetate (4) [13] and aldehydes 5a–n following the litera-
ture procedure (Scheme 1) [12]. First, we tried to prepare
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624ꢀ ꢀM. Drev et al.: Transformations of β-aryl-N-Cbz-α,β-didehydro-α-amino esters
COOMe
NHCbz
occurred upon 24 h, the reaction mixtures were simply
stirred for another 48 h, whereupon the precipitates
were formed and collected by filtration. Only in the reac-
tion of 2′-methoxycinnamate 1b, the precipitate was not
formed. In the cyclizations of ortho-hydroxy- (1a) and
ortho-benzyloxy-substituted cinnamate 1c, the expected
3-pyrazolidinones 2a and 2c were obtained in 32% and
18% yield, respectively. Meanwhile, cyclization of methyl
2′-chlorocinnamate 1d afforded a 4:1 mixture of the pyra-
zolidinone 2d and the 1-aminohydantoin derivative 6d,
whereas reaction of 2′-nitrocinnamate 1e furnished only
the corresponding hydantoin 6e in 48% yield. These
unexpected results prompted us to treat also the acrylates
1f–n in the same way. Reactions of 1f, g, k gave mixtures of
pyrazolidinones 2f, g, k and hydantoins 6f, g, k, whereas
3-(pyridyl)acrylates 1h–j furnished the hydantoins 6h–j
in 3–50% yields. Formation of hydantoins 6f and 6g as by-
products was not detected previously upon significantly
shorter reaction times [11]. Acrylates 1m and 1n produced
only the corresponding 3-pyrazolidinones 2m and 2n,
which was in agreement with the literature data [7, 11]. No
precipitate was formed in the reaction of dehydrotrypto-
phan ester 1l (Scheme 1, Table 1).
N2H4·H2O
FG
FG = halogen, OR, NHR, COR
1
H
H
N
N
O
O
HN
HN
Annelation
NHCbz
FG
X
3
2
X = O, NR
Fig. 1:ꢀPlanned synthesis of tricyclic pyrazolidinones 3 via
annelation of ortho-substituted 5-aryl group.
3-pyrazolidinones 2a–e as the representative central
intermediates. It is noteworthy that our previous reactions
of acrylates 1 with hydrazine hydrate were carried out
only for a few hours and furnished only the correspond-
ing pyrazolidinones 2 upon workup by filtration [7–11].
Besides, chromatographic workup was not suitable for
isolation of quite polar 1,2-unsubstituted 4-acylamino-
3-pyrazolidinones 2 [5–11]. Following our previous exam-
ples [7–11], the acrylates 1a–e bearing an ortho-substituent
at the 5-aryl group were treated with 3 equiv. of hydrazine
hydrate in ethanol at r.t. Somewhat expectedly, reac-
tions of 1a–e were slower than known reactions of their
ortho-unsubstituted analogues [7–11]. As no precipitation
Intrigued by these findings, we became interested
in selectivity of the above transformations. Acrylates
1a–n were treated with 3 equiv of hydrazine hydrate in
ethanol at r.t. for 3 days followed by evaporative workup.
1H NMR spectra of the crude reaction mixtures were
taken in [D6]DMSO to determine the ratio of formed prod-
ucts. Surprisingly, the unexpected N-Cbz-3-arylalanine
hydrazides 7 were also formed in addition to the expected
O
P
CO2Me
NHCbz
MeO
MeO
4
Table 1:ꢀExperimental data for compounds 2 and/or 6 isolated upon
workup by filtration.
RCHO (5a–n),
CH2Cl2, DBU, r. t.
[Refs. 11, 12]
Entryꢁ Compound
ꢁ R
ꢁ Yield (%) ꢁ
2:6ꢁ Ref.
1
2
3
4
5
6
7
8
9
ꢂ 1a, 2a, 5a, 6a ꢂ 2-Hydroxyphenyl
ꢂ 1b, 2b, 5b, 6b ꢂ 2-Methoxyphenyl
ꢂ
ꢂ
32a ꢂ 100:0a ꢂ [11]
CO2Me
NHCbz
c
b ꢂ
b ꢂ
c
c
c
R
ꢂ 1c, 2c, 5c, 6c
ꢂ 2-Benzyloxyphenyl ꢂ
18ꢂ 100:0ꢂ
65ꢂ 81:19ꢂ
48ꢂ 0:100ꢂ
1a–n
ꢂ 1d, 2d, 5d, 6d ꢂ 2-Chlorophenyl
ꢂ 1e, 2e, 5e, 6e ꢂ 2-Nitrophenyl
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
N2H4·H2O, EtOH, r.t., 3 days
workup by filtration
ꢂ 1f, 2f, 5f, 6f
ꢂ 3-Nitrophenyl
17 ꢂ 88:12ꢂ [11]
57 ꢂ 93:7 ꢂ [11]
ꢂ 1g, 2g, 5g, 6g ꢂ 4-Nitrophenyl
ꢂ 1h, 2h, 5h, 6h ꢂ 2-Pyridyl
c
50ꢂ 0:100ꢂ
O
H2
N
c
1
HN
4
ꢂ 1i, 2i, 5i, 6i
10 ꢂ 1j, 2j, 5j, 6j
ꢂ 3-Pyridyl
ꢂ 4-Pyridyl
5ꢂ 0:100ꢂ
5′
5
O
NH2
c
N3
3
and/or
3ꢂ 0:100ꢂ
R
5
c
HN
4
11 ꢂ 1k, 2k, 5k, 6k ꢂ 2-Furyl
79ꢂ 71:29ꢂ
2
1
R
NHCbz
O
c
12 ꢂ 1l, 2l, 5l, 6l
ꢂ N-Boc-1H-indol-3-yl ꢂ
b ꢂ
b ꢂ
2a, c, d, f, g, k, m, n
6d–k
13 ꢂ 1m, 2m, 5m, 6m ꢂ Phenyl
14 ꢂ 1n, 2n, 5n, 6n ꢂ Isopropyl
ꢂ
ꢂ
80a ꢂ 100:0a ꢂ [10]
80a ꢂ 100:0a ꢂ [7]
Scheme 1:ꢀIsolation of 3-pyrazolidinones 2 and 1-aminohydantoins
6 upon treatment of 1 with hydrazine hydrate followed by filtration
workup.
aIn agreement with the literature data. bNo precipitate was formed.
cThis paper.
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M. Drev et al.: Transformations of β-aryl-N-Cbz-α,β-didehydro-α-amino estersꢃ
ꢃ625
pyrazolidinones 2 and hydantoins 6. In most cases, the
hydantoins were the minor components, whereas pyrazo-
lidinones 2 and hydrazides 7 were the major components
of the product mixtures (Scheme 2, Table 2). In summary,
three reactions were completely selective (cf. Table 2): (a)
treatment of dehydroleucine ester 1n afforded only the
3-pyrazolidinone 2n (Entry 14) [7]; (b) reaction of 2-pyridyl
substituted acrylate 1h gave the hydantoin 6h as the only
product (Entry 8); and (c) its 4-pyridyl analogue 1j gave
only the corresponding hydrazide 7j (Entry 10). Although
the selectivity pattern could not be clearly discerned,
preferential formation of hydrazides 7 was observed in
the reactions of acrylates 1d–g, i, j bearing electron-with-
drawing substituents at the 5-aryl group (Table 2, Entries
4–7, 9, 10), whereas reactions of 2′-hydroxy- and 2′-alkoxy-
Table 2:ꢀRatio of products 2, 6, and 7 upon prolonged treatment of
1 with hydrazine hydrate.
Entryꢁ
Compound ꢁ
R
ꢁ
2:6:7a
1
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
2a, 6a, 7a
2b, 6b, 7b
2c, 6c, 7c
2d, 6d, 7d
2e, 6e, 7e
2f, 6f, 7f
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
2-Hydroxyphenyl
2-Methoxyphenyl
ꢂ
ꢂ
45:15:40b
40:15:45b
35:10:55b
0:21:79
0:35:65
34:8:58
30:4:66
0:100:0
0:3:97
0:0:100
55:45:0b
67:33:0b
65:18:17b
100:0:0
2
3
2-Benzyloxyphenyl ꢂ
4
2-Chlorophenyl
2-Nitrophenyl
3-Nitrophenyl
4-Nitrophenyl
2-Pyridyl
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
5
6
7
2g, 6g, 7g
2h, 6h, 7h
2i, 6i, 7i
8
9
3-Pyridyl
10
11
12
13
2j, 6j, 7j
4-Pyridyl
2k, 6k, 7k
2l, 6l, 7l
2-Furyl
N-Boc-1H-indol-3-yl ꢂ
2m, 6m, 7mꢂ
Phenyl
Isopropyl
ꢂ
ꢂ
cinnamates 1a–c gave comparable amounts of 2 and 7 14
(Table 2, Entries 1–3). In the reactions of acrylates 1k–n
with ortho-unsubstituted electron-rich groups the pyra-
2n, 6n, 7n
ꢂ
aDetermined from the 1H NMR spectra of the crude reaction mixtures.
bBecause of overlapping signals, the ratio of products could not be
clearly discerned.
zolidinones 2k–n were formed predominantly (Table 2,
Entries 11–14).
The next important issue was the tentative reac-
tion pathway (mechanism) of these transformations. hydantoin 6d. (Hydantoin 6d was obtained upon crys-
Ring transformations of 3-pyrazolidinones and their tallization of a 4:1 mixture of 2d and 6d from ethanol.)
azomethine imine derivatives into N-aminohydantoins Similarly, the 5-phenyl analogue 2m gave the 3-pheny-
have been reported previously [10]. To get a deeper lalanine hydrazide 7m as the only product, whereas the
insight into the reaction pathway, further experiments 5-isopropyl analogue 2n did not react with hydrazine
were performed. First, treatment of a 2:1 mixture of hydrate (Scheme 3).
5-(2-chlorophenyl)-3-pyrazolidinone 2d and hydantoin
The results of the above experiments were in agree-
6d with 3 equiv of hydrazine hydrate in ethanol at r.t. for ment with formation of the pyrazolidinones 2 and hydan-
7 days furnished a 2:1 mixture of the hydrazide 7d and toins 6 as the two primary products in the reaction of
acrylates 1 with excess hydrazine hydrate. Thus, hydan-
toins 6 were presumably formed directly from 1 and not
via ring transformation of the pyrazolidinone intermedi-
CO2Me
ate 2. This is supported by the unchanged ratio of 7d and
R
NHCbz
1a–n
6d compared to the ratio of starting compounds 2d and 6d
(cf. Scheme 3). Similarly, the above unchanged ratio of 7d
and 6d was in agreement with formation of 3-arylalanine
hydrazides 7 through reductive cleavage of the benzylic
C–N bond in the pyrazolidinones 2. This is additionally
supported by the non-reactivity of the 5-alkyl substituted
pyrazolidinone 2ndevoid of benzylic C–N bond. The whole
reaction sequence can thus be rationalized by initial com-
petitive 1,4- and 1,2-addition of hydrazine hydrate to the
unsaturated ester 1 to give the acrylohydrazide intermedi-
ate 8 (Scheme 4, Path A) and the β-hydrazino alaninate 9
(Scheme 4, Path B). The hydrazide 8 cyclizes by condensa-
tion to the carbamate group to give the hydantoin 6 [10],
whereas cyclization of the hydrazine 9 to the ester group
leads to the pyrazolidinone 2 [8]. Upon prolonged treat-
ment with hydrazine hydrate, the relatively weak ben-
zylic C–N bond in 5-aryl-3-pyrazolidinones 2 undergoes
N2H4·H2O, EtOH, r.t., 3 days
workup by evaporation
O
H
N
O
NH2
HN
R
N
R
HN
and/or
NHCbz
O
2a–c, f, g, k–n
6a–i, k–m
CONHNH2
NHCbz
R
7a–g, i, j, m
Scheme 2:ꢀFormation of 3-pyrazolidinones 2, 1-aminohydantoins
6, and hydrazines 7 upon prolonged treatment of 1 with hydrazine
hydrate followed by evaporative workup.
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626ꢀ ꢀM. Drev et al.: Transformations of β-aryl-N-Cbz-α,β-didehydro-α-amino esters
H
O
H2N NH2
N
O
HN
Ar
NH2
O
N
+
Ar
O
HN
NHCbz
O
6d
2d
R
NHCbz
2d:6d = 2:1
1
H2N NH2
Path A
1,2-Addition
N2H4·H2O (3 eq),
EtOH, r. t., 7 days
Path B
Ar = 2-ClC6H4
1,4-Addition
O
O
NH2
NH
H2N
HN
OMe
O
CONHNH2
NHCbz
NH2
N
Ar
+
Ar
HN
OBn
R
HN
O
R
NHCbz
7d
6d
7d:6d = 2:1
O
9
8
H
N
Cyclization
Cyclization
O
HN
O
H
N
R
NHCbz
2m, n
O
NH2
HN
N
or/and
R
N2H4·H2O (3 eq.)
EtOH, r. t., 7 days
HN
R
NHCbz
O
6
2
2n, R = i-Pr
2m, R = Ph
N2H4·H2O
R = aryl
reductive C–N bond cleavage
H
N
O
CONHNH2
NHCbz
HN
CONHNH2
Ph
NHCbz
R
NHCbz
7
7m
2n
No conversion
Scheme 4:ꢀPlausible reaction pathway for formation of 2, 6, and 7.
Scheme 3:ꢀControl experiments performed to establish the reaction
pathway.
nitrogen atom, keeping the hydrazino group away from
reductive ring opening to give the N-Cbz-3-arylalanine the ester function. Besides, the same ring nitrogen could
hydrazide 7 (Scheme 4).
also promote β-elimination from 9h leading to starting
In light of this explanation, the generally observed compound 1h or, alternatively, ring opening of the pyra-
preferential formation of 2 and 7 is explainable by pre- zolidinone 2h to give the hydrazide 8h, which cyclizes
dominant 1,4-addition of hydrazine hydrate to acrylate into 6h (Scheme 5).
1 in the beginning of the reaction. This is in agreement
The structures of all novel compounds 1c, 1j, 1l, 2c,
with selective formation of 7i and 7j from 3-pyridy- 2d, 2f, 2g, 2k, and 6c–k were determined by spectro-
lacrylates 1i and 1j, due to activation of the β-position scopic methods (IR, 1H and 13C NMR, HRMS). These novel
by the electron-withdrawing 3- and 4-pyridyl groups. compounds were not obtained in analytically pure form.
13
Meanwhile, selective transformation of their 2-pyridyl Their identities were confirmed by C NMR and HRMS.
analogue 1h into hydantoin 6h does not fit into such an Compounds 1c, 1j, 1l, 2c, 6e, and 6h–j were obtained
explanation because the β-position in 1h is activated sim- and characterized as single components, whereas com-
ilarly as in 1i and 1j. Therefore, there has to be another pounds 2d/6d, 2f/6f, 2g/6g, 2k/6k were obtained as
explanation for this exceptional selectivity. A plausible inseparable mixtures of compounds and were character-
rationale is based on specificity of acrylate 1h with basic ized as such. The (Z)-configuration around the exocyclic
ring nitrogen atom at the ortho-position of the pyridyl Cꢀ=ꢀC double bond of hydantoins 6 was determined on the
residue. Thus, cyclization of the 1,2-adduct 8h should be basis of the characteristic chemical shift for the 5′-H, δ ꢀ=ꢀ
much faster than cyclization of the Michael adduct 9h, 6.45–6.65 ppm, which was in agreement with the litera-
which is hindered by intramolecular Cꢀ=ꢀN···H–N hydro- ture data for closely related (Z)-5-benzylidenehydantoins
gen bond between the hydrazino group and the pyridine [14, 15].
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M. Drev et al.: Transformations of β-aryl-N-Cbz-α,β-didehydro-α-amino estersꢃ
ꢃ627
H
CO2Me
NHCbz
4 Experimental section
N
+ N2H4·H2O
Melting points were determined on a Stanford Research
Systems MPA100 OptiMelt automated melting point
system. The NMR spectra were obtained on a Bruker
1h
1,2-Addition
O
1,4-Addition
1
Avance III UltraShield 500 plus at 500 MHz for H and at
126 MHz for 13C nucleus, respectively, using CDCl3 and [D6]
DMSO as solvents with TMS as the internal standard. Mass
spectra were recorded on an Agilent 6224 Accurate Mass
TOF LC/MS spectrometer and IR spectra on a Bruker FTIR
Alpha Platinum ATR spectrophotometer. Microanalyses
were performed on a Perkin-Elmer CHN Analyzer 2400 II.
Flash column chromatography (FC), was performed on
silica gel (Fluka, Silica gel 60, particle size 35–70 μm).
Aldehydes 5a, b, d–k, m, n, DBU, and hydrazine
hydrate are commercially available. Methyl 2-{[(benzy-
loxy)carbonyl]amino}-2-(dimethoxyphosphoryl)acetate
(4) [13], 2-benzyloxybenzaldehyde (2c) [16], 1-tert-butoxy-
carbonyl-1H-indole-3-carbaldehyde (5l) [17], 3-substituted
methyl 2-(benzyloxycarbonylamino)acrylates 1a, b, d–i,
k, m, n [9–12], and 3-pyrazolidinones 2m [10] and 2n [7]
were prepared according to the literature procedures.
H
N
H
N N
NHNH2
CO2Me
NHCbz
H
H
N
NHCbz
9h
8h
6h
Cyclization
H
N
O
HN
NHCbz
H
N
2h
Scheme 5:ꢀProposed rationale for chemoselective formation of
hydantoin 6h.
3 Conclusion
4.1 General procedure for the
synthesis of 3-substituted methyl
2-(benzyloxycarbonylamino)-acrylates
1c, j, l
Treatment of easily available N-Cbz-3-aryl-2,3-dehydro-
alanine esters 1 with excess hydrazine hydrate leads to
three types of products, 3-pyrazolidinones 2, 1-amino-
5-benzylidenehydantoins 6, and/or N-Cbz-3-arylalanine
hydrazides 7. 3-Pyrazolidinones 2 and 1-aminohydantoins
6 are the primary cyclization products, which are pre-
sumably formed from 1 via competitive 1,4- and 1,2-addi-
tion of hydrazine hydrate followed by cyclization of the
respective adducts 8 and 9. Meanwhile, 3-arylalanine
hydrazides 7 are formed from the corresponding 5-aryl-
3-pyrazolidinones 2 by reductive cleavage of the ben-
zylic C(5)–N(1) bond. The selectivity is dependent on the
reaction time and on the 3-aryl substituent in starting
acrylate 1. Upon short reaction times and workup by filtra-
tion, sparingly soluble pyrazolidinones 2 and/or hydan-
toins 6 are obtained. Prolonged reaction time followed
by evaporative workup lead to mixtures of 2, 6, and 7.
High overall selectivity was observed only in cyclizations
of β-pyridylacrylates 1h–j, which furnished the respec-
tive hydantoin 6h and hydrazides 7i and 7j as the only
products. In summary, the present study shows that the
Compounds 1c, j, l were prepared following a slightly mod-
ified literature procedures [11, 12]. A mixture of 4 (16.6 g,
50 mmol), CH2Cl2 (200 mL), DBU (7.83 mL, 52.5 mmol), and
5 (50 mmol) was stirred at 0°C or r.t. for 0.5–24 h.
Workup A: Volatile components were evaporated
in vacuo, and the residue was diluted with AcOEt (150 mL)
and washed with 1 M aqueous NaHSO4 (2 ꢀ×ꢀ 70 mL). The
combined organic phase was dried over anhydrous Na2SO4
and filtered, and the filtrate was evaporated in vacuo to
give 1.
Workup B: The reaction mixture was poured directly
onto a stabilized column and the product was isolated by
FC (silica gel, 3 ꢀ×ꢀ 15 cm, EtOAc). Fractions containing the
product were combined and evaporated in vacuo to give 1.
The following compounds were prepared in this
manner:
course of reactions of dehydroalanine esters 1 with hydra- 4.1.1 Methyl 2-benzyloxycarbonylamino-3-(2-
zine hydrate depends on the β-substituent of the starting
acrylate 1. These reactions do not lead only to the corre-
benzyloxyphenyl)acrylate (1c)
sponding 3-pyrazolidinones 2 as believed previously, but Prepared from 4 (0.993 g, 3 mmol) and 2-benzyloxyben-
rather to mixtures of products 2, 6, and 7.
zaldehyde 5c (636 μL, 3 mmol), r.t., 12 h, workup A. Yield:
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628ꢀ ꢀM. Drev et al.: Transformations of β-aryl-N-Cbz-α,β-didehydro-α-amino esters
1.23 g (98%) of a light orange oil. – IR (ATR): v ꢀ=ꢀ 3314, 4.2 Synthesis of 5-substituted (4R*,5R*)-
3063, 3032, 2950, 1708 (Cꢀ=ꢀO), 1640 (Cꢀ=ꢀO), 1597, 1577,
4-benzyloxycarbonylamino-3-pyrazolid-
1484, 1450, 1435, 1380, 1303, 1219, 1162, 1139, 1112, 1048,
inones 2a, c–k, m, n and (Z)-3-amino-5-
1
1025, 910, 847, 478, 733, 695, 623 cm−1. – H NMR (500
(benzylidene)imidazolidine-2,4-diones
MHz, CDCl3): δ ꢀ=ꢀ 3.83 (s, 3H, OCH3), 5.11 and 5.15 (2s, 1:1,
6d, f, g, k
4H, 2 ꢀ×ꢀ OCH2Ph), 6.95–7.01 (m, 2H, 1H of Ar, NH), 7.28–7.45
(m, 12H, 12 H of Ar), 7.52 (m, 2H, 1H of Ar, 3-H) ppm. –
Hydrazine hydrate (98%, 150 μL, 3 mmol) was added to
13C NMR (126 MHz, CDCl3): δ ꢀ=ꢀ 52.6, 67.3, 70.9, 113.2, 121.2,
a stirred solution of 1 (1 mmol) in EtOH (5 mL) and the
123.3, 125.4, 125.5, 127.3, 127.3, 128.1, 128.2, 128.3, 128.5,
mixture was stirred at r.t. for 3 days. The precipitate was
128.6, 128.7, 130.0, 130.5, 136.4, 156.3, 165.8 ppm. – HRMS
collected by filtration and washed with EtOH (2 ꢀ×ꢀ 3 mL) to
((+)-ESI): m/z ꢀ=ꢀ 418.1647 (calcd. 418.1649 for C25H24NO5,
give 2 or/and 6. The following compounds were prepared
in this manner:
+
[M+H] ).
4.1.2 Methyl 2-benzyloxycarbonylamino-3-(4-pyridyl)
4.2.1 (4R*,5R*)-4-benzyloxycarbonylamino-5-(2-
acrylate (1j)
hydroxyphenyl)-3-pyrazolidinone (2a)
Prepared from 4 (0.993 g, 3 mmol) and pyridine-4-car-
Prepared from 1a (0.327 g, 1 mmol). Yield: 0.105 g (32%)
baldehyde 5j (600 μL, 3 mmol), 0°C, 0.5 h, workup B.
of white crystals. Physical and spectral data of 2a were in
Yield: 0.936 g (100%) of a yellow oil. – IR (ATR): v ꢀ=ꢀ
agreement with the literature data [11].
3306, 3150, 3064, 3032, 2951, 2892, 2846, 1714 (Cꢀ=ꢀO), 1646
(Cꢀ=ꢀO), 1598, 1547, 1497, 1454, 1435, 1412, 1385, 1331, 1307,
1266, 1216, 1140, 1040, 990, 885, 850, 814, 769, 736, 696,
4.2.2 (4R*,5R*)-4-benzyloxycarbonylamino-5-(2-
621 cm−1. – 1H NMR (500 MHz, CDCl3): δ 3.82 (s, 3H, OCH3),
benzyloxyphenyl)-3-pyrazolidinone (2c)
5.11 (s, 2H, OCH2), 7.15 (s, 1H, 3-H), 7.29–7.39 (m, 7H, Ph,
2′-H, 6′-H), 8.11 (s, 1H, NH), 8.45–8.61 (m, 2H, 3′-H, 5′-H)
Prepared from 1c (417 g, 1 mmol). Yield: 75 mg (18%) of
ppm. – 13C NMR (126 MHz, CDCl3): δ ꢀ=ꢀ 52.6, 67.2, 123.2,
white crystals. M.p. 135°C–138°C. – IR (ATR): v ꢀ=ꢀ 3360,
127.3, 128.0, 128.1, 128.1, 128.3, 135.7, 141.3, 149.7, 153.7, 165.0
3284, 3237, 3183, 3065, 3033, 1714 (Cꢀ=ꢀO), 1695 (Cꢀ=ꢀO), 1602,
ppm. – HRMS ((+)-ESI): m/z ꢀ=ꢀ 313.1181 (calcd. 313.1183 for
1589, 1528, 1500, 1465, 1446, 1409, 1383 1350, 1294, 1241,
+
C17H17N2O4, [M+H] ).
1202, 1176, 1152, 1105, 1044, 1028, 1004, 957, 940, 903, 857,
−1
1
804, 771, 752, 735, 693, 640 cm . – H NMR (500 MHz,
CDCl3): δ ꢀ=ꢀ 4.62 (t, J ꢀ=ꢀ 10.1 Hz, 1H, 5-H), 4.74 (t, J ꢀ=ꢀ 10.5 Hz,
1H, 4-H), 4.89–4.99 (m, 2H, OCH2Ph), 5.16 (s, 2H, OCH2Ph),
5.20 (d, J ꢀ=ꢀ 11.5 Hz, 1H, 1-H), 6.97 (t, J ꢀ=ꢀ 7.5 Hz, 1H, 1H of Ar),
7.09 (d, J ꢀ=ꢀ 8.3 Hz, 1H, 1H of Ar), 7.25–7.39 (m, 10H, 10H of
Ar), 7.49 (d, J ꢀ=ꢀ 8.2 Hz, 2H, 2H of Ar), 7.67 (d, J ꢀ=ꢀ 9.2 Hz, 1H,
NHCbz), 9.45 (br s, 1H, 2-H) ppm. – 13C NMR (126 MHz, [D6]
DMSO): δ ꢀ=ꢀ 56.5, 61.5, 65.5, 69.3, 112.7, 120.6, 124.6, 127.2,
127.6, 127.8, 127.8, 128.3, 128.3, 128.7, 129.4, 136.8, 137.0,
156.0, 156.8, 173.0 ppm. – HRMS ((+)-ESI): m/z ꢀ=ꢀ 418.1759
4.1.3 Methyl 2-benzyloxycarbonylamino-3-(1-tert-
butoxycarbonyl-1H-indol-3-yl)acrylate (1l)
Prepared from 4 (0.662 g, 2 mmol) and 1-tert-butoxycar-
bonyl-1H-indole-3-carbaldehyde 5l (0.490 g, 2 mmol), r.t.,
24 h, workup B. Yield: 0.930 g (50%) of a yellow oil. – IR
(ATR): v ꢀ=ꢀ 3110, 3001, 2951, 2902, 1684 (Cꢀ=ꢀO), 1597, 1558,
1533, 1498, 1464, 1439, 1404, 1387, 1364, 1326, 1302, 1282,
1249, 1221, 1200, 1187, 1167, 1134, 1090, 1077, 1009, 957, 919,
894, 857, 827, 813, 800, 791, 777, 759, 713, 670, 657, 628 cm−1.
+
(calcd. 418.1761 for C24H24N3O4, [M+H] ).
1
– H NMR (500 MHz, CDCl3): δ ꢀ=ꢀ 1.65 (s, 9H, tBu), 3.83 (s,
3H, OCH3), 5.15 (s, 2H, OCH2Ph), 6.37 (br s, 1H, NHCO), 7.23–
7.40 (m, 7H, Ph, 5′-H, 6′-H), 7.66 (s, 1H, 3-H), 7.70 (d, J ꢀ=ꢀ 7.8 4.2.3 (4R*,5R*)-4-benzyloxycarbonylamino-5-(2-
Hz, 1H, 4′-H), 7.96 (s, 1H, 3′-H), 8.14 (d, J ꢀ=ꢀ 8.1 Hz, 1H, 7′-H)
ppm. – 13C NMR (126 MHz, CDCl3): δ ꢀ=ꢀ 28.2, 52.7, 65.5, 67.7,
84.7, 114.2, 115.5, 119.1, 123.4, 125.3, 127.1, 127.7, 127.7, 128.3,
128.4, 128.6, 128.7, 129.5, 136.0, 149.3, 165.7 ppm. – HRMS
chlorophenyl)-3-pyrazolidinone (2d) and (Z)-3-
amino-5-(2-chlorobenzylidene)imidazolidine-2,4-
dione (6d)
((+)-ESI): m/z ꢀ=ꢀ 451.1860 (calcd. 451.1864 for C25H27N2O6, Prepared from 1d (345 mg, 1 mmol). Yield: 224 mg (69%)
+
[M+H] ).
of a white solid, 2d:6d ꢀ=ꢀ 81:19. – IR (ATR): v ꢀ=ꢀ 3246, 3064,
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ꢁꢀꢀꢀ
M. Drev et al.: Transformations of β-aryl-N-Cbz-α,β-didehydro-α-amino estersꢃ
ꢃ629
3032, 2999, 2949, 2949, 2894, 1727 (Cꢀ=ꢀO), 1690 (Cꢀ=ꢀO), 1642 1585, 1523, 1467, 1453, 1413, 1350, 1290, 1232, 1213, 1186, 1147,
(Cꢀ=ꢀO), 1589, 1504, 1456, 1431, 1368, 1297, 1262, 1231, 1146, 1100, 1079, 1062, 1030, 964, 918, 897, 833, 816, 771, 755, 736,
1086, 1062, 996, 936, 915, 873, 843, 823, 779, 748, 719, 698, 686, 643, 609 cm−1.
665 cm−1.
NMR and MS data for compound 2f [11]: 1H NMR (500
1
NMR and MS data for compound 2d: H NMR (500 MHz, [D6]DMSO): δ ꢀ=ꢀ 4.43 (t, J ꢀ=ꢀ 9.8 Hz, 1H, 4-H), 4.49 (t,
MHz, [D6]DMSO): δ ꢀ=ꢀ 4.47 (t, J ꢀ=ꢀ 9.7 Hz, 1H, 5-H), 4.81 (t, J ꢀ=ꢀ 10.6 Hz, 1H, 5-H), 5.02 (s, J ꢀ=ꢀ 6.4 Hz, 2H, OCH2), 5.67
J ꢀ=ꢀ 10.5 Hz, 1H, 4-H), 4.98 and 5.02 (2d, 1:1, J ꢀ=ꢀ 12.4 Hz, 2H, (d, J ꢀ=ꢀ 10.6 Hz, 1H, 1-H), 7.29–7.39 (m, 5H, Ph), 7.70 (t, J ꢀ=ꢀ
OCH2Ph), 5.34 (d, J ꢀ=ꢀ 10.5 Hz, 1H, 1-H), 7.29–7.41 (m, 6H, 8.0 Hz, 1H, 1H of Ar), 7.83 (d, J ꢀ=ꢀ 8.8 Hz, 1H, NHCbz), 7.90
6H of Ar), 7.48 (dd, J ꢀ=ꢀ 7.7, 1.6 Hz, 1H, 1H of Ar), 7.71 (dd, J ꢀ=ꢀ (d, J ꢀ=ꢀ 7.8 Hz, 1H, 1H of Ar), 8.21 (dd, J ꢀ=ꢀ 7.9, 2.2 Hz, 1H, 1H
7.5, 2.0 Hz, 1H, 1H of Ar), 7.75 (br d, J ꢀ=ꢀ 9.3 Hz, 2H, NHCbz, of Ar), 8.35 (t, J ꢀ=ꢀ 2.0 Hz, 1H, 1H of Ar), 9.65 (s, 1H, 2-H)
13
13
1H of Ar), 9.52 (s, 1H, 2-H) ppm. – C NMR (126 MHz, [D6] ppm. – C NMR (126 MHz, [D6]DMSO): δ ꢀ=ꢀ 57.9, 65.0, 65.7,
DMSO): δ ꢀ=ꢀ 57.2, 62.6, 65.6, 127.4, 127.8, 127.9, 128.4, 128.7, 121.9, 123.1, 127.7, 127.9, 128.4, 130.2, 134.1, 136.8, 139.4, 147.9,
129.7, 129.9, 134.1, 134.2, 136.8, 156.0, 172.2 ppm. – HRMS 156.2, 172.0 ppm. – HRMS ((+)-ESI): m/z ꢀ=ꢀ 357.1189 (calcd.
+
((+)-ESI): m/z ꢀ=ꢀ 348.1102 (calcd. 348.1109 for C17H19ClN3O3, 357.1193 for C17H17N4O5, [M+H] ).
+
1
[M+H] ).
NMR data for compound 6f: H NMR (500 MHz, [D6]
1
NMR and MS data for compound 6d: H NMR (500 DMSO): δ ꢀ=ꢀ 4.91 (s, 2H, NH2), 6.64 (s, 1H, CH), 7.77 (t, J ꢀ=ꢀ
MHz, [D6]DMSO): δ ꢀ=ꢀ 4.93 (s, 2H, NH2), 6.65 (s, 1H, CH), 8.0 Hz, 1H, 1H of Ar), 8.04 (d, J ꢀ=ꢀ 7.8 Hz, 1H, 1H of Ar), 8.13
7.35–7.43 (m, 3H, 3H of Ar), 7.55 (dd, J ꢀ=ꢀ 7.6, 1.6 Hz, 1H, 1H (dd, J ꢀ=ꢀ 8.2, 1.7 Hz, 1H, 1H of Ar), 8.45 (t, J ꢀ=ꢀ 2.0 Hz, 1H,
13
13
of Ar), 10.80 (s, 1H, 1-H) ppm. – C NMR (126 MHz, [D6] 1H of Ar), 9.36 (s, 1H, 1-H) ppm. – C NMR (126 MHz, [D6]
DMSO): δ ꢀ=ꢀ 104.2, 127.6, 127.8, 129.7, 130.0, 130.3, 130.7, DMSO): δ ꢀ=ꢀ 106.3, 123.7, 127.7, 127.9, 130.1, 135.4, 147.9, 148.2,
133.2, 154.7, 162.8 ppm. – HRMS ((+)-ESI): m/z ꢀ=ꢀ 238.0377 163.4, 166.7 ppm.
+
(calcd. 238.0383 for C10H9ClN3O2, [M+H] ).
4.2.6 (4R*,5R*)-4-benzyloxycarbonylamino-5-(4-
4.2.4 (Z)-3-amino-5-(2-nitrobenzylidene)imidazolidine-
nitrophenyl)-3-pyrazolidinone (2g) and (Z)-3-
amino-5-(4-nitrobenzylidene)imidazolidine-2,4-
dione (6g)
2,4-dione (6e)
Prepared from 1e (89 g, 0.25 mmol). Yield: 30 mg (48%) of
yellow crystals. M.p. 180°C (decomp). – IR (ATR): δ ꢀ=ꢀ 3331, Prepared from 1g 178 mg, 0.5 mmol). Yield: 100 mg (57%)
3252, 3171, 2970, 1773 (Cꢀ=ꢀO), 1714 (Cꢀ=ꢀO), 1658 (Cꢀ=ꢀO), 1619, of a yellow solid, 2g:6g ꢀ=ꢀ 93:7. – IR (ATR): v ꢀ=ꢀ 3337, 3224,
1600, 1588, 1572, 1517, 1439, 1340, 1308, 1248, 1211, 1177, 3176, 3082, 1715 (Cꢀ=ꢀO), 1693 (Cꢀ=ꢀO), 1604, 1518, 1454, 1419,
1131, 1077, 1045, 949, 882, 859, 785, 747, 721, 694, 673, 660, 1374, 1345, 1286, 1238, 1208, 1179, 1147, 1107, 1083, 1049,
1
642, 606 cm−1. – H NMR (500 MHz, [D6]DMSO): δ ꢀ=ꢀ 4.92 1013, 976, 948, 917, 889, 867, 846, 836, 776, 747, 723, 696,
(s, 2H, NH2), 6.61 (s, 1H, CH), 7.31 (ddd, J ꢀ=ꢀ 7.5, 4.8, 0.9 Hz, 685, 630 cm−1.
1H, 1H of Ar), 7.63 (d, J ꢀ=ꢀ 7.8 Hz, 1H, 1H of Ar), 7.84 (td, J ꢀ=ꢀ
NMR and MS data for compound 2g [11]: 1H NMR (500
7.7, 1.8 Hz, 1H, 1H of Ar), 8.66 (d, J ꢀ=ꢀ 4.0 Hz, 1H, 1H of Ar), MHz, [D6]DMSO): δ ꢀ=ꢀ 4.40 (t, J ꢀ=ꢀ 9.8 Hz, 1H, 5-H), 4.49 (t,
10.52 (s, 1H, 1-H) ppm. – 13C NMR (126 MHz, [D6]DMSO): δ ꢀ=ꢀ J ꢀ=ꢀ 10.5 Hz, 1H, 4-H), 5.01 and 5.03 (2d, 1:1, J ꢀ=ꢀ 12.6 Hz, 2H,
106.1, 122.5, 125.6, 129.3, 129.3, 137.2, 149.5, 153.7, 153.7, 162.7 OCH2), 5.68 (d, J ꢀ=ꢀ 10.6 Hz, 1H, 1-H), 7.29–7.40 (m, 5H, Ph),
ppm. – HRMS ((+)-ESI): m/z ꢀ=ꢀ 249.0619 (calcd. 249.0618 7.72 (d, J ꢀ=ꢀ 8.7 Hz, 2H, 2H of Ar), 7.84 (d, J ꢀ=ꢀ 9.0 Hz, 1H,
+
for C10H9N4O4, [M+H] ).
NHCbz), 8.25 (d, J ꢀ=ꢀ 8.7 Hz, 2H, 2H of Ar), 9.66 (s, 1H, 2-H)
ppm. – 13C NMR (126 MHz, [D6]DMSO): δ ꢀ=ꢀ 58.0, 65.1, 65.7,
123.7, 127.8, 127.9, 128.4, 128.5, 136.8, 144.9, 147.3, 156.2, 172.0
ppm. – HRMS ((+)-ESI): m/z ꢀ=ꢀ 357.1190 (calcd. 357.1193 for
4.2.5 (4R*,5R*)-4-benzyloxycarbonylamino-5-(3-
nitrophenyl)-3-pyrazolidinone (2f) and (Z)-3-
amino-5-(3-nitrobenzylidene)imidazolidine-2,4-
dione (6f)
+
C17H17N4O5, [M+H] ).
NMR data for compound 6g: 1H NMR (500 MHz, [D6]
DMSO): δ ꢀ=ꢀ 4.94 (s, 2H, NH2), 6.62 (s, 1H, CH), 7.89 (d,
J ꢀ=ꢀ 8.8 Hz, 2H, 2H of Ar), 8.22 (d, J ꢀ=ꢀ 8.9 Hz, 2H, 2H of
13
Prepared from 1f (178 mg, 0.5 mmol). Yield: 30 mg (17%) Ar), 9.37 (br s, 1H, NH), ppm. – C NMR (126 MHz, [D6]
of a yellow solid, 2f:6f ꢀ=ꢀ 88:12. – IR (ATR): v ꢀ=ꢀ 3368, 3285, DMSO): δ ꢀ=ꢀ 106.2, 123.0, 123.8, 127.3, 130.3, 146.2, 155.1,
3231, 3186, 3095, 2945, 1775 (Cꢀ=ꢀO), 1694 (Cꢀ=ꢀO), 1661 (Cꢀ=ꢀO), 163.0 ppm.
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ꢀꢀꢀꢁ
630ꢀ ꢀM. Drev et al.: Transformations of β-aryl-N-Cbz-α,β-didehydro-α-amino esters
4.2.7 (Z)-3-amino-5-(2-pyridylmethylidene)
4.2.10 (4R*,5R*)-4-benzyloxycarbonylamino-5-(2-furyl)-
3-pyrazolidinone (2k) and (Z)-3-amino-5-(furan-2-
ylmethylene)imidazolidine-2,4-dione (6k)
imidazolidine-2,4-dione (6h)
Prepared from 1h (599 mg, 1,9 mmol). Yield: 194 mg (50%)
of white crystals. M.p. 200°C (decomp). – IR (ATR): v ꢀ=ꢀ 3318, Prepared from 1k (150 mg, 0.5 mmol). Yield: 106 mg (79%)
3207, 3034, 1760 (Cꢀ=ꢀO), 1706 (Cꢀ=ꢀO), 1661 (Cꢀ=ꢀO), 1615, 1575, of a beige solid, 2k:6k ꢀ=ꢀ 71:29. – IR (ATR): v ꢀ=ꢀ 3338, 3291,
1556, 1470, 1432, 1394, 1356, 1261, 1238, 1182, 1151, 1136, 1090, 3208, 3175, 2942, 1718 (Cꢀ=ꢀO), 1695 (Cꢀ=ꢀO), 1661 (Cꢀ=ꢀO), 1534,
935, 917, 883, 789, 749, 715, 669, 622, 604 cm−1. – 1H NMR (500 1499, 1466, 1453, 141, 1403, 1356, 1285, 1238, 1196, 1160,
MHz, [D6]DMSO): δ ꢀ=ꢀ 4.93 (s, 2H, NH2), 6.62 (s, 1H, CH), 7.31 1134, 1060, 1027, 1016, 964, 936, 903, 884, 827, 804, 773,
(ddd, J ꢀ=ꢀ 7.6, 4.8, 1.2 Hz, 1H, 5′-H), 7.63 (dt, J ꢀ=ꢀ 7.9, 1.1 Hz, 1H, 739, 694, 675, 646, 612 cm−1.
1
3′-H), 8.66 (ddd, J ꢀ=ꢀ 4.9, 1.9, 0.9 Hz, 1H, 6′-H), 8.84 (td, J ꢀ=ꢀ 7.7,
NMR and MS data for compound 2k: H NMR (500
13
1.9 Hz, 1H, 4′-H), 10.51 (br s, 1H, NH) ppm. – C NMR (126 MHz, [D6]DMSO): δ ꢀ=ꢀ 4.38 (t, J ꢀ=ꢀ 11.2 Hz, 1H, 5-H), 4.52 (t,
MHz, [D6]DMSO): δ ꢀ=ꢀ 106.1, 122.5, 125.6, 129.3, 137.2, 149.5, J ꢀ=ꢀ 11.2, 1H, 4-H), 5.03 (s, 2H, OCH2Ph), 5.39 (d, J ꢀ=ꢀ 11.2 Hz,
153.7, 153.7, 162.7 ppm. – HRMS ((+)-ESI): m/z ꢀ=ꢀ 205.0719 1H, 1-H), 6.46 (dd, J ꢀ=ꢀ 3.3, 1.8 Hz, 1H, 4′-H), 6.49 (d, J ꢀ=ꢀ 3.3
+
(calcd. 205.072 for C9H9N4O2, [M+H] ). – C9H8N4O2 (204.2): Hz, 1H, 3′-H), 7.29–7.38 (m, 5H, Ph), 7.67 (d, J ꢀ=ꢀ 1.3 Hz, 1H,
calcd. C 52.94, H 3.95, N 27.44; found: C 52.90, H 3.48, N 26.80. 5′-H), 7.69 (d, J ꢀ=ꢀ 9.3 Hz, 1H, NHCbz), 9.51 (s, 1H, 2-H) ppm.
– 13C NMR (126 MHz, [D6]DMSO): δ ꢀ=ꢀ 56.1, 59.7, 65.7, 108.5,
110.6, 112.7, 113.5, 127.8, 128.3, 136.8, 143.3, 156.2, 172.4
4.2.8 (Z)-3-amino-5-(3-pyridylmethylidene)
ppm. – HRMS ((+)-ESI): m/z ꢀ=ꢀ 302.1121 (calcd. 302.1135 for
+
imidazolidine-2,4-dione (6i)
C15H16N3O4, [M+H] ).
1
NMR data for compound 6k: H NMR (500 MHz, [D6]
Prepared from 1i (178 mg, 0.5 mmol). Yield: 5 mg (5%) of DMSO): δ ꢀ=ꢀ 4.89 (s, 2H, NH2), 6.45 (s, 1H, CH), 6.64 (dd, J ꢀ=ꢀ
orange crystals. M.p. 180°C (decomp). – IR (ATR): v ꢀ=ꢀ 3359, 3.2, 1.6 Hz, 1H, 4′-H), 6.95 (d, J ꢀ=ꢀ 3.4 Hz, 1H, 3′-H), 7.78 (d,
3285, 3197, 3052, 2764, 2165, 2096, 1966, 1771 (Cꢀ=ꢀO), 1735 J ꢀ=ꢀ 1.3 Hz, 1H, 5′-H), 9.04 (s, 1H, 1-H) ppm. – 13C NMR (126
(Cꢀ=ꢀO), 1718 (Cꢀ=ꢀO), 1703 (Cꢀ=ꢀO), 1658 (Cꢀ=ꢀO), 1593, 1536, 1514, MHz, [D6]DMSO): δ ꢀ=ꢀ 97.7, 112.5, 115.9, 120.2, 127.6, 148.9,
1496, 1440, 1377, 1334, 1280, 1267, 1238, 1215, 1174, 1130, 154.2, 162.6 ppm.
1032, 961, 915, 879, 854, 843, 812, 778, 750, 708, 691, 652,
634, 607 cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ ꢀ=ꢀ 4.93 (s,
2H, NH2), 6.56 (s, 1H, CH), 7.43 (dd, J ꢀ=ꢀ 8.0, 4.8 Hz, 1H, 5′- 4.2.11 (4R*,5R*)-4-benzyloxycarbonylamino-5-phenyl-3-
H), 8.06 (dt, J ꢀ=ꢀ 8.1, 2.0 Hz, 1H, 6′-H), 8.50 (dd, J ꢀ=ꢀ 4.8, 1.5
Hz, 1H, 4′-H), 8.80 (d, J ꢀ=ꢀ 2.3 Hz, 1H, 2′-H), 9.00 (s, 1H, 1-H)
pyrazolidinone (2m)
ppm. – 13C NMR (126 MHz, [D6]DMSO): δ ꢀ=ꢀ 105.7, 123.7, 129.0, Prepared from 1m (0.327 g, 1 mmol). Yield: 0.147 g (47%)
135.8, 148.8, 150.4, 154.7, 162.7, 169.2 ppm. – HRMS ((+)-ESI): of white crystals. Physical and spectral data of 2m were in
+
m/z ꢀ=ꢀ 205.0720 (calcd. 205.0720 for C9H9N4O2, [M+H] ).
agreement with the literature data [10].
4.2.9 (Z)-3-amino-5-(4-pyridylmethylidene)
4.2.12 (4R*,5R*)-4-benzyloxycarbonylamino-5-
imidazolidine-2,4-dione (6j)
isopropyl-3-pyrazolidinone (2n)
Prepared from 1j (178 mg, 0.5 mmol). Yield: 3 mg (3%) of Prepared from 1n (0.275 g, 1 mmol). Yield: 0.200 g (72%)
yellow crystals. M.p. 200°C (decomp). – IR (ATR): v ꢀ=ꢀ 3273, of white crystals. Physical and spectral data of 2n were in
3195, 3031, 2168, 1788 (Cꢀ=ꢀO), 1730 (Cꢀ=ꢀO), 1703 (Cꢀ=ꢀO), 1659 agreement with the literature data [7].
(Cꢀ=ꢀO), 1599, 1550, 1535, 1514, 1498, 1453, 1438, 1366, 1333,
1267, 1238, 1205, 1182, 1137, 1073, 1025, 998, 959, 935, 903,
1
845, 813, 778, 746, 724, 691, 669, 642, 610 cm−1. – H NMR 4.3 Synthesis of (RS)-benzyl (1-hydrazinyl-
(500 MHz, [D6]DMSO): δ ꢀ=ꢀ 4.93 (s, 2H, NH2), 6.47 (s, 1H,
1-oxo-3-phenylpropan-2-yl)carbamate
CH), 7.56–7.62 (m, 2H, 2′-H, 6′-H), 8.51–8.65 (m, 2H, 3′-H,
(7m)
13
5′-H), 10.39 (br s, 1H, 1-H) ppm. – C NMR (126 MHz, [D6]
DMSO): δ ꢀ=ꢀ 105.8, 123.3, 136.8, 140.1, 150.0, 154.9, 162.8 Hydrazine hydrate (98%, 75 μL, 1.5 mmol) was added to
ppm. – HRMS ((+)-ESI): m/z ꢀ=ꢀ 205.0723 (calcd. 205.0720 a stirred suspension of 2m (0.156 g, 0.5 mmol) in EtOH
+
for C9H9N4O2 [M+H] ).
(5 mL) and the mixture was stirred at r.t. for 7 days.
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ꢁꢀꢀꢀ
M. Drev et al.: Transformations of β-aryl-N-Cbz-α,β-didehydro-α-amino estersꢃ
ꢃ631
[2] B. Stanovnik, J. Svete, Chem. Rev. 2004, 104, 2433.
Volatile components were evaporated in vacuo to afford
7m. Yield: 157 mg (100%) of a colorless resin. – IR (ATR):
v ꢀ=ꢀ 3310, 3034, 2946, 1690 (Cꢀ=ꢀO), 1646 (Cꢀ=ꢀO), 1529, 1384,
[3] J. M. Humphrey, A. R. Chamberlin, Chem. Rev. 1997, 97, 2243.
[4] U. Schmidt, A. Lieberknecht, J. Wild, Synthesis 1988, 20, 159.
[5] H. Dorn, Chem. Heterocycl. Compd. USSR 1981, 17, 1.
[6] R. M. Claramunt, J. Elguero, Org. Prep. Proced. Int. 1991, 23,
273.
1
1372, 1311, 1257, 1128, 1040, 910, 752, 698, 655 cm−1. – H
NMR (500 MHz, [D6]DMSO): δ ꢀ=ꢀ 2.76 (dd, J ꢀ=ꢀ 13.7, 10.4 Hz,
1H, 3-Ha), 2.90 (dd, J ꢀ=ꢀ 13.7, 4.6 Hz, 1H, 3-Hb), 4.18 (ddd,
J ꢀ=ꢀ 10.4, 8.7, 4.5 Hz, 1H, 2-H), 4.27 (s, 2H, NH2), 4.92 (s, 2H,
OCH2Ph), 7.16–7.37 (m, 10H, 2 ꢀ×ꢀ Ph), 7.54 (d, J ꢀ=ꢀ 8.7 Hz, 1H,
NHCH), 9.23 (s, 1H, NHNH2) ppm. – 13C NMR (126 MHz, [D6]
DMSO): δ ꢀ=ꢀ 37.8, 55.0, 65.2, 126.3, 127.5, 127.7, 128.1, 128.3,
128.3, 129.2, 137.0, 138.1, 155.7, 170.8 ppm. – HRMS ((+)-ESI):
[7] A. Novak, A. Testen, J. Bezenšek, U. Grošelj, M. Hrast, M.
Kasunič, S. Gobec, B. Stanovnik, J. Svete, Tetrahedron 2013,
69, 6648.
[8] J. Svete in Stereochemistry Research Trends (Eds.: M. A. Horvat,
J. H. Golob), Nova Science Publishers, New York, 2008, chapter
5, p. 129. (open access item).
[9] U. Grošelj, J. Svete, ARKIVOC 2015, Part (vi), 175.
[10] A. Novak, J. Bezenšek, U. Grošelj, A. Golobič, B. Stanovnik,
J. Svete, ARKIVOC 2011, Part (vi), 18.
+
m/z ꢀ=ꢀ 314.1498 (calcd. 314.1499 for C17H20N3O3, [M+H] ).
[11] A. Novak, M. štefanič, U. Grošelj, M. Hrast, M. Kasunič, S.
Gobec, B. Stanovnik, J. Svete, Helv. Chim. Acta 2014, 97, 245.
[12] U. Schmidt, H. Griesser, H. Lietenberger, A. Lieberknecht, R.
Mangold, R. Meyer, B. Riedl, Synthesis 1992, 24, 487.
[13] U. Schmidt, A. Lieberknecht, J. Wild, Synthesis 1984, 16, 53.
[14] T. Sau-Fun, A. Kok-Peng, F. Yoke-Fan, J. Chem. Soc., Perkin
Trans. 2 1986, 1941.
Acknowledgments: We are grateful to the Slovenian
Research Agency (Program Code P1-0179) for the financial
support.
References
[1] U. Kazmaier in Amino Acids, Peptides and Proteins in Organic
Chemistry: Modified Amino Acids, Organocatalysis and
Enzyme, Vol. 2 (Ed.: A. B. Hughes), Wiley-VCH, Weinheim, 2009,
chapter 1, p. 1.
[15] N. A. Meanwell, H. R. Roth, E. C. R. Smith, D. L. Wedding, J. J. K.
Wright, J. Org. Chem. 1991, 56, 6897.
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